Field of the Invention
This invention relates to an oral solid dosage form containing nanoparticles. This invention also relates to a process of formulating the oral solid dosage form using fish gelatin.
Description of Related Art
Oral drug delivery typically requires drug products to release drug molecules to form a solution in the gastrointestinal tract, so that drug can be absorbed across the gut wall and enter the systemic circulation. For reasons of product efficacy and safety, drug molecule release should take place in a controlled manner, with a release profile that meets the therapeutic requirements of the product. Most oral products aim for fast and complete release of drug in the gastrointestinal tract in order to generate a fast onset of action along with the most efficient delivery of drug molecule to the biological target.
Experts in the fields of drug discovery and drug development have noted that new drug molecules under development in recent years increasingly possess poor water solubility. Estimates of more than 40% of new drug molecules exhibiting poor water solubility have been documented. See Water Insoluble Drug Formulation, Rong Liu ed., CRC Press, 2nd ed., p. 1 (2008). The prevalence of poorly water soluble drug molecules creates a significant challenge for development of viable oral drug products. The reason for this problem is that poor water solubility can limit the speed and extent to which drug molecules can enter solution or dissolve in the gastrointestinal tract. The technical challenge of formulating poorly water soluble drugs can actually limit some drugs from reaching the market, thus denying patients new products.
A proven approach to improving the dissolution properties of poorly water soluble drug molecules is to reduce particle size of the solid drug, as increased surface area of the dissolving drug particles correlates with increased dissolution rates. Reduction of particle size to the submicron or nanoparticle range produces dramatic increases in surface area and thus the greatest opportunity for dissolution rate enhancement via this mechanism. Therefore, nanoparticle drug delivery can provide faster dissolution, improved bioavailability and ultimately enhanced clinical efficacy.
The advantages of using nanoparticles for oral drug delivery, especially for dosing poorly soluble drug molecules, are well known and have been documented for over 20 years. Despite this, the present inventors believe there are only about four commercial pharmaceutical oral solid dosage formulations in the United States that allege to contain nanoparticles, which suggests that there are technical challenges associated with developing stable nanoparticulate products. Known commercial oral solid dosage formulations are Rapamune® (Wyeth Pharmaceuticals Inc., Philadelphia, Pa.), Emend® (Merck & Co., Whitehouse Station, N.J.), TriCor® (Abbott Laboratories, North Chicago, Ill.), and Triglide™ (Sciele Pharma Inc., Atlanta, Ga.).
The primary problem with developing solid nanoparticle drug delivery systems is the tendency of nanoparticles to re-aggregate either rapidly during processing or on extended storage, which results in increased particle size and thus reduced efficacy. The aggregation problem is typically overcome using stabilizing excipients categorized as steric stabilizers (e.g., synthetic polymers) and/or electrostatic stabilizers (e.g., surfactants). The known commercial products noted above all use wet milling technology to create nanosuspensions, followed by spray drying of the nanosuspension onto a solid substrate phase of a size and dimension suitable for processing into a single-unit dosage form (e.g., tablet or capsule). Spray drying is a general term that may include recognized processes such as spray coating or spray granulation, whereby a nanosuspension is sprayed onto a solid substrate under conditions that cause rapid volatilization and removal of the liquid component to leave dried solid phase coated on the solid substrate.
Freeze-drying is an alternate process to spray drying that can convert a nanosuspension into the solid state, although this technology is not known to have been used in conventional nanoparticulate products. The aggregation problem is greater for a system that undergoes freeze-drying due to the intense physical forces experienced during the freezing and lyophilization steps of the freeze-drying process. Conventional solutions to address the aggregation problem typically involve complex manufacturing procedures, requiring isolation of a dried nanoparticle intermediate material and/or adjustment of the excipient composition after milling but before unit dosage form processing.
U.S. Pat. No. 5,932,245 describes the preparation of colloidal nanosols using a precipitation method with gelatin or its derivatives acting as nanoparticle stabilizer. The process involves stabilizing a colloidally dispersed solution of the active substance by partly or fully setting the iso-ionic point (equivalent to a neutral charge) between the gelatin and the surface charged active substance particles. There is, however, no disclosure or suggestion of using fish gelatin as a nanoparticle stabilizer during nanomilling and/or as a nanoparticle stabilizer during freeze-drying.
U.S. Pat. Nos. 5,145,684 and 5,510,118 describe wet milling processes to generate nanoparticles of low solubility drugs that use non-crosslinked surface modifiers to maintain particle size in the submicron range. Preferred surface modifiers include nonionic and anionic surfactants, but both disclosures indicate that surface modifiers may be selected from an extended list of pharmaceutical excipients that includes gelatin. There is, however, no disclosure or suggestion of using fish gelatin as a nanoparticle stabilizer during nanomilling and/or as a nanoparticle stabilizer during freeze-drying.
U.S. Patent Application Publication No. 2005/0031691 discloses compositions containing an active agent of less than about 2000 nm, at least one surface stabilizer, and a gel-forming agent, wherein gelatin functions as a water-retention aid to facilitate gelling in the dosage form. This system is claimed to provide compositions that can be molded into a variety of dosage forms. There is, however, no disclosure or suggestion of using fish gelatin as a nanoparticle stabilizer during nanomilling and/or as a nanoparticle stabilizer during freeze-drying.
The use of freeze-drying to convert a liquid nanosuspension into solid product with favorable dispersion properties (interchangeably described as fast-dispersing, fast-dissolving, fast disintegrating, rapidly disintegrating) is disclosed in WO99/38496, U.S. Pat. No. 5,302,401, WO 2004/043440, and U.S. Pat. No. 6,316,029. All disclosures indicate that gelatin may be included in the dosage form. However, there is no disclosure or suggestion regarding the specific benefits associated with one source of gelatin, such as gelatin extracted from fish.
WO99/38496 discloses gelatin among a long list of potential fast-dissolve matrix forming agents; however, there is no disclosure or suggestion of using fish gelatin during nanosuspension formation or as the nanoparticle stabilizer during manufacture of the fast-dissolve matrix.
U.S. Pat. No. 5,302,401 discloses the use of gelatin as a nanoparticle surface modifier stabilizer. However, a cryoprotectant (defined in U.S. Pat. No. 5,302,401 as an agent that protects from nanoparticle agglomeration caused by lyophilization) is disclosed as a separate component, which is preferably a carbohydrate. In addition, the cryoprotectant molecule is added to the pre-formed nanosuspension, suggesting that formula modifications between nanomilling and freeze-drying are critical to the successful formation of freeze-dried nanoparticles.
WO 2004/043440 also discloses the use of one or more surface stabilizer molecules, such as gelatin, in combination with pullulan (a polymeric carbohydrate) to form fast-disintegrating tablets containing nanoparticles using a lyophilization process. Pullulan is added to the pre-prepared nanosuspension before freeze-drying, with no description of adding pullulan prior to nanosuspension formation either as a surface stabilizer or for any other function. There is, however, no disclosure or suggestion of using fish gelatin as a nanoparticle stabilizer during nanomilling and/or as a nanoparticle stabilizer during freeze-drying.
U.S. Pat. No. 6,316,029 discloses the use of at least one surface stabilizer (with gelatin identified as an example) in combination with a water-soluble or water dispersible excipient (with gelatin identified as an example) processed to form a rapidly disintegrating dosage form containing nanoparticles. However, it does not disclose or suggest using fish gelatin as a nanoparticle stabilizer during nanomilling and/or as a nanoparticle stabilizer during freeze-drying. In addition, it does not disclose the need for a stabilizing agent to ensure nanoparticle size is retained during freeze-drying.
U.S. Pat. No. 6,709,669 discloses the preparation of fast-dispersing dosage forms using freeze-drying that contain pharmaceutical active ingredient and fish gelatin as a carrier. The advantages of using fish gelatin in this manner are identified as faster disintegration times, better taste and mouthfeel, and shorter manufacturing process times. However, it does not disclose or suggest a solid dosage form containing nanoparticles or the advantages of using fish gelatin in particle size reduction to form nanoparticles or freeze-drying of nanoparticle systems. In addition, there is no disclosure or suggestion of fish gelatin's stabilization properties of any kind, including nanoparticle stabilization.
The present inventors are unaware of any prior art that teaches or suggests the formation of a nanoparticulate solid oral dosage form using fish gelatin as both a nanoparticle stabilizer during nanomilling as well as a nanoparticle stabilizer during freeze-drying. Also, there is no known disclosure or suggestion of a process to manufacture nanoparticulate solid oral dosage forms without the need for significant adjustment of the qualitative and quantitative excipient composition between the nanomilling and freeze-drying steps. For example, information in the public domain regarding the manufacturing process of Rapamune® describes that the pharmaceutically active ingredient sirolimus is reduced by wet milling to nanometer dimensions in the presence of a stabilizer. Then, the nanodispersion is added to a sugar coating suspension and coated onto inert tablet cores previously overcoated with shellac. Another example is the manufacturing process for Emend®, for which a slurry of water, the pharmaceutically active ingredient aprepitant, and hydroxypropylcellulose (steric stabilizer) and sodium lauryl sulfate (ionic stabilizer) are media-milled to form a colloidal dispersion. To convert to a solid dosage form, sucrose is added to the dispersion followed by spraying the dispersion onto microcrystalline cellulose beads. Both processes clearly involve substantial changes in the qualitative (i.e., number of excipients) and quantitative (i.e., ratio of excipients) between the step of forming a nanodispersion and the step of forming a solid dosage form containing nanoparticles. See, product-specific scientific discussion documents available from the European Medicines Agency website at http://www.emea.europa.eu/. As can be seen, current commercial compositions and processes for nanoparticulate products are complex. Further, those skilled in the art will recognize that these compositions or processes are not appropriate for all pharmaceutically active ingredients.
Currently, a need exists for an alternate oral solid dosage form containing nanoparticles that is produced by a process that does not involve complex manufacturing procedures.